The possible role of cell cycle regulators in multistep process of HPV-associated cervical carcinoma

Pathology Department, National Cancer Institute, Cairo University, 1st Kasr El-Aini st. Cairo, Egypt.
BMC Clinical Pathology 02/2007; 7(1):4. DOI: 10.1186/1472-6890-7-4
Source: PubMed


Human papillomavirus (HPV) 16 and 18 are associated with cervical carcinogenesis through an interaction between HPV oncogenic proteins and cell cycle regulatory genes. However, the exact pathogenetic mechanisms are not determined yet.
We investigated 43 invasive squamous cell carcinoma (ISCC), 38 CIN III, 11 CINII and 18 CINI for cyclin D1, cyclin E, CDK4, p53, mdm-2, p21(waf), p27, p16(INK4A), Rb and Ki-67 aberrations using immunohistochemistry and molecular techniques. Twenty samples of normal cervical tissues (NCT) were taken as a control.
There was a significant increase in the expression of Ki-67, cyclin E, CDK4, p16(INK4A), Rb (p= 0.003, 0.001, 0.001, 0.01) and a significant decrease in p27(KIP1) from NCT to ISCC (p = 0.003). Increased cyclin D1, p21(waf), p53, mdm-2 expression, homozygous deletion (HZD) and promoter methylation (PM) of the Rb were detected in CINIII and ISCC only. On univariate analysis; tumor size, differentiation, lymph node status, FIGO stage, Ki-67, cyclin D1, p53 and p27(KIP1) are significantly associated with reduced overall survival (OS) while on multivariate analysis; only FIGO stage, Ki-67, cyclin D1, p53 and p27(KIP1) were significant.
1) Aberrations involving p27(KIP1), cyclin E, CDK4, p16(INK4A) are considered early events in HPV 16 and 18-associated cervical carcinoma, whereas cyclin D1 and p53 pathway abnormalities are considered late events. 2) Immunohistochemical tests for p16(INK4A) and cyclin E, could help in early diagnosis of cervical carcinoma. 3) Only FIGO stage p53, cyclin D1, p27(KIP1) and Ki-67 are independent prognostic factors that might help in predicting outcome of cervical cancer patients.

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Available from: Abdel-Rahamn Zekri, Oct 03, 2015
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    • "P53 acts as a tumor suppressor protein and has the capacity to induce the expression of p21 [7]. The blockage of the p53 functions leads to inactivity of p21–CDKI [8]. The overexpression of p16 ink4a –CDKI is related to the negative feedback induced by this in the situation when E7 hr-HPV oncoproteins bind pRb [9]. "
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    ABSTRACT: Objective: The aim of this research was to assess the immunofluorescence expression (IFE) of cell cycle regulators p16ink4a, p21, p27, in association with proliferation and prognosis factors Ki-67, p53 respectively, in cell cultures, obtained from different types of cervical intraepithelial lesions. The final purpose was to distinguish a best marker able to identify with high accuracy the high-grade squamous intraepithelial lesion. Materials and Methods: The study was carried out on 68 epithelial cell cultures. Three senior specialists have analyzed 500 cells/case individually. The statistic analysis for correlation between used markers has been performed. Results: The study batch revealed a very low expression of investigated parameters (<1%) in negative cases for malignancy and intraepithelial lesion (NMIL), a progressive exponential expression in low-grade squamous intraepithelial lesion (LSIL), and a very high expression in high-grade squamous intraepithelial lesion (HSIL) and invasive squamous cervical carcinoma (ISCC). Ki-67 and p53 were overexpressed in nuclei both in LSIL and HSIL. A slightly direct correlation between p21 and Ki-67 (r=0.35, p<0.001) was observed in HSIL. Statistically significant correlations were noticed between some markers: p16ink4a and p27 (r=0.4, p=0.03), p16ink4a and Ki-67 (r=-0.4, p=0.002). Conclusions: The most reliable parameters for assessing HSIL and ISCC proved to be Ki-67 and p16ink4a. Both were with percentages and intensity of IFE around 100% and higher immunoexpression within the nucleus of cell cultures. Our study reveals that p27 cyclin inhibitor was not reliable in differentiating between LSIL and HSIL.
    Romanian journal of morphology and embryology = Revue roumaine de morphologie et embryologie 12/2013; 54(3 Suppl):725-734. · 0.66 Impact Factor
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    • "A high concentration of a cyclin D1 and CDK4 complex can result in the functional inactivation of retinoblastoma protein (pRb) and this pathway is commonly targeted in various malignancies (27). In cervical cancer, binding of HPV E7 protein to Rb leads to release of E2F transcription factor omitting the role of cyclin D1, and CDK4 has been shown a stepwise increase from normal to tumor tissues occurs, indicating an important role at an early stage of transformation of HPV infected cervical epithelium (28, 29). In this study, expression of CDK4 was up regulated in cervical cancer tissue and this finding suggests that CDK4 is closely correlated with carcinogenesis of cervical cancer. "
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    ABSTRACT: Cervical cancer is the second most common gynecological cancer among Korean women. While nationwide screening program has developed, the pathogenesis of cervical cancer is unknown. The aim of this study was to compare the protein expression profiles between cervical squamous carcinomas and normal cervical tissues in order to identify proteins that are related to the cancer. Three cervical cancer tissue samples and three normal cervical tissue samples were obtained and protein expression was compared and was identified in the samples with the use of matrix assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF-MS). A total of 20 proteins that showed up-regulated expression in the cervical cancer tissue samples were selected and identified. Seven proteins were matched to allograft inflammatory factor 1 (AIF-1), actine-like protein 2 (ALP2), brain type fatty acid-binding protein (B-FABP), NCK adaptor protein 1 (NCK-1), islet cell autoantigen 1 (ICA69), cationic trypsinogen (PRSS1), and cyclin-dependent kinase 4 (CDK4), but the remaining 13 proteins were unidentifiable. After confirmation by RT-PCR, Western blotting and immunohistochemistry, we found that B-FABP, NCK-1, and CDK4 were related to the pathogenesis of cervical cancer. These proteins are suggested as candidates of new pathological tumor markers for cervical cancer.
    Journal of Korean medical science 12/2012; 27(12):1479-85. DOI:10.3346/jkms.2012.27.12.1479 · 1.27 Impact Factor
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    • "Recently, it has been proposed that p27 Kip1 protein works in a negative feedback loop regulating Grb2 in response to mitogen stimulation, inhibiting the Ras signal transduction pathway (Moeller et al., 2003). Other reports have shown that low levels of p27 Kip1 protein correlate with tumor progression and poor patient survival in many human cancers (Abukhdeir and Park 2008; Bahnassy et al., 2007; Catzavelos et al., 1997; Mori et al., 1997). On the other hand, during cancer development, it has been observed that viral oncoproteins from papillomavirus, adenovirus or SV40, target cell cycle proteins and manipulate the cell towards the transformed phenotype. "
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    ABSTRACT: E5 oncoprotein activity from high risk human papillomaviruses (HPVs) is associated with growth factor receptor signaling, but the function of this protein is not well understood. In this study, we investigated the role of HPV-16 E5 on the cell cycle progression during EGF-stimulation. Wild-type and NIH 3T3 cells over-expressing human EGF-receptor were transfected with HPV-16 E5 gene and the cell cycle progression was characterized. This analysis showed that the E5-expressing cells increased DNA synthesis (S-phase) by around 40%. Cell cycle protein analysis of E5-expressing cells showed a reduction in the half-life of p27(Kip1) protein as compared to control cells (18.4 vs. 12.7 h), an effect that was enhanced in EGF-stimulated cells (12.8 vs. 3.6 h). Blockage of EGF-receptor activity abrogated E5 signals as well as p27(Kip1) down-regulation. These results suggest that E5 and the EGF-receptor cooperate to enhance cell cycle entry and progression through regulating p27(Kip1) expression at protein level.
    Virology 02/2010; 400(1):44-52. DOI:10.1016/j.virol.2010.01.009 · 3.32 Impact Factor
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